1. Field of the Invention
The present invention relates to agents for treating irritable bowel syndrome. The present invention also relates to methods for treating irritable bowel syndrome.
2. Discussion of the Background
Irritable bowel syndrome (IBS) is a functional bowel disorder in which abdominal pain or discomfort is associated with defecation or a change in bowel habit, and with features of disordered defecation. This disorder is not accompanied by organic disorders whose symptoms can be explained (e.g., inflammation, tumor and the like), but the result of the functional abnormality of lower digestive tracts. The symptoms are long-lasting or come and go over time. According to the Rome III published in 2006 (Gastroenterology, 2006, vol. 130, pp. 1480-1491), IBS is classified based on the predominant stool pattern into four subtypes of IBS with diarrhea (IBS-D), IBS with constipation (IBS-C), mixed IBS (IBS-M) which shows both diarrhea and constipation, and unsubtyped IBS (IBS-U). Though IBS is not a fatal disease, it has been found that it causes difficulty for patients in carrying out social activities because they undergo behavioral restriction depending on the symptoms. The prevalence of IBS in the general population is estimated from 10% to 15% in North America, Europe and Asia, and its annual morbidity rate is from 1% to 2%. In addition, IBS is a highly frequent disorder occupying from 20 to 50% of the gastrointestinal outpatients. Its male to female ratio is predominant in female because it is 1:2 regardless of the human race, and it has higher prevalence rate in the younger generation.
Since mental or physical stress is strongly implicated in the onset of the symptom of IBS, it is regarded as a stress-related disease. Actually, it is known that emotional stress worsens the symptoms of IBS patients.
As the drug therapy of IBS, anticholinergics or tricyclic antidepressants are used for abdominal pain/discomfort, and conventional anti-diarrheal drugs or laxatives are used for diarrhea or constipation, respectively, but they are merely symptomatic treatments and their effects are not clear. Polycarbophil calcium is an agent whose effects can be expected for both diarrhea and constipation in Japan, but the efficacy is very limited because not only there is an abdominal swelling feeling at the initial stage of its administration but also it requires time for expressing the effects. Minor tranquilizers and antidepressants are used when anxiety and tension are considerably increased due to stress, but they are administered at a relatively lower doses, so that their effects are also limited. As described above, a sufficiently effective therapeutic method for IBS has not been established.
A 5-HT3 receptor antagonist, alosetron, and a 5-HT4 receptor agonist, tegaserod, are medical agents for IBS-D and IBS-C, respectively. These agents improve bowel movement by regulating movement of intestines, and the onset of effect is quick. However, alosetron shows only an improvement rate of about 50% for abdominal symptoms and diarrhea, constipation occurs in 30 to 35% of the patients and it causes ischemic colitis (including fatal cases) as a serious side effect, so that its use is limited. As in the case of alosetron, the efficacy of tegaserod is not sufficient, and the use of tegaserod is also limited to severe IBS patients because of its risk for cardiovascular side effects. Accordingly, it is considered that the need for an IBS-treating agent remains unmet.
In recent years, it has been reported that micro-inflammation, infection, or allergy in the intestinal tracts are also important as risk factors of IBS, in addition to the mental and physical stresses. It has been considered classically that the mast cells are activated only by an antigenic stimulation, but it is now considered the cells are activated also by a stress, a micro-inflammation and nervous system mediators. The activation of mast cells induces the release of granular mediators such as histamine, lipid mediators, and cytokines that can modulate intestinal functions. These mechanisms have been recently assumed to impact to the pathogenesis of IBS.
Under such circumstances, there are the following reports suggesting the effects of mast cell degranulation inhibitors.
Clinical and Experimental Allergy, 1991, vol. 21, pp. 569-572; The American Journal of Gastroenterology, 1992, vol. 87 (1), pp. 55-57; and Scandinavian Journal of Gastroenterology, 1995, vol. 30, pp. 535-541 disclose that a mast cell degranulation inhibitor, sodium cromoglycate (cromolyn), was effective when administered at a dose of from 1,500 to 2,000 mg per day to specific IBS patients having food allergy.
Journal of Veterinary Science, 2004, vol. 5 (4), pp, 319-324 discloses that doxantrazole which has a mast cell degranulation inhibitory activity is effective for rat intestinal hyperesthesia.
Also, International Publication WO 95/21611 discloses that a histamine H1 antagonist ketotifen inhibited the secretion of rat mast cell protease II (RMCPII). International Publication WO 95/21611 discloses that sodium cromoglycate is classified as a phosphatase inhibitor and not included in the disclosed invention though it has the mast cell degranulation inhibitory activity. Moreover, though a great variety of compounds including an anti-female hormone agent and a histamine H3 antagonist are defined as mast cell degranulation inhibitors in addition to a histamine H1 antagonist, their inhibitory activity of mast cell degranulation are unknown. So that it cannot be said that this reference clarifies whether or not the mast cell degranulation inhibitors other than histamine H1 antagonists are effective for the treatment of IBS.
On the other hand, it has been reported that N-(1H-tetrazol-5-yl)-1-phenoxy-4H-quinolizin-4-one-3-carboxamide has mast cell degranulation inhibitory activity (see, Japanese Journal of Pharmacology, 1993, vol. 63, pp. 73-81) and is effective for the treatment of allergy and ulcer (see, EP-0 157 346 A), cough and phlegm (see, JP-A-6-256187), pain, conjunctivitis and rheumatoid arthritis (see, International Publication WO 94/07491) and interstitial pneumonia, inflammatory bowel disease and vascular hypertrophy (see, EP-0811378 A), but its effects for IBS have not been reported.
Thus, there remains a need for agents and methods which are effective for treating IBS.